Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing

Rowlands, CF; Allen, S; Balma&#241;a, J; Domchek, SM; Evans, DG; Hanson, H; Hoogerbrugge, N; James, PA; Nathanson, KL; Robson, M; Tischkowitz, M; Foulkes, WD; Turnbull, C

Author(s): Rowlands, CF; Allen, S; Balmaña, J; Domchek, SM; Evans, DG; Hanson, H; Hoogerbrugge, N; James, PA; Nathanson, KL; Robson, M; Tischkowitz, M; Foulkes, WD; Turnbull, C;
Details: Publication Year 2024-10,Volume 35,Issue #10,Page 892-901
Journal Title: Annals of Oncology
Publication Type: Research article
Abstract: BACKGROUND: Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included. PATIENTS AND METHODS: Weighted meta-analysis was carried out for three population-based case-control studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101 397 women with breast cancer and 312 944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, 'population-type' breast cancer cases and their association with breast cancer and its subtypes. RESULTS: Meta-analysed odds ratios (ORs) and frequencies of PVs in 'population-type' breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in 'population-type' breast cancer cases was very low for 'syndromic' BCSGs TP53 (1 in 1844), STK11 (1 in 11 525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11. CONCLUSIONS: These metrics reflecting 'population-type' breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.
Publisher: Elsevier
Keywords: Humans; *Breast Neoplasms/genetics/epidemiology/pathology; Female; *Genetic Predisposition to Disease; *Germ-Line Mutation; *Genetic Testing/methods; Case-Control Studies; Fanconi Anemia Complementation Group N Protein/genetics; BRCA1 Protein/genetics; BRCA2 Protein/genetics; Checkpoint Kinase 2/genetics; Genetic Association Studies; Ataxia Telangiectasia Mutated Proteins/genetics; Ubiquitin-Protein Ligases/genetics; DNA-Binding Proteins/genetics; Tumor Suppressor Proteins; breast cancer; case–control; mainstream genetic testing; meta-analysis; multigene panel testing
Department(s): Familial Cancer Centre
Publisher's Version: https://doi.org/10.1016/j.annonc.2024.07.244
Open Access at Publisher's Site: https://doi.org/10.1016/j.annonc.2024.07.244
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-10-01 07:37:02

Last Modified: 2024-10-01 07:37:20